Synthesis of polycyclic procyanidins

ABSTRACT

The invention provides compounds that are A-type procyanidins. The compounds can be prepared by reacting flavylium salts with catechins or analogs thereof, for example, under anhydrous conditions in alcohol.

RELATED APPLICATION

This application is a continuation under 37 C.F.R. 1.53 (b) of U.S.patent application Ser. No. 11/275,756, filed Jan. 26, 2006 now U.S.Pat. No. 7,615,649, the content of which is incorporated herein byreference in its entirety.

STATEMENT OF GOVERNMENT RIGHTS

The invention was made with a grant from the Government of the UnitedStates of America (USDA/ARS Grant No. 58-3K95-5-1073). The Governmenthas certain rights to the invention.

BACKGROUND OF THE INVENTION

Despite extensive diabetes research, the prevention and control of type2 diabetes mellitus (type 2 DM) remain unclear. Diet has been shown toplay a definite role in the onset of type 2 DM, and the diets commonlyconsumed in the United States and other westernized countries appear toincrease the incidence of diabetes (J. S. Carter et al., Ann. Int. Med.,125, 221 (1996)). The high refined sugar and high fat content of U.S.diets are likely to be partly responsible, but the low intake oftraditional herbs, spices, and other plant products may also beinvolved. The recommended use of plants in the treatment of diabetesdates back to approximately 1550 BCE (A. M. Gray et al., Br. J. Nutr.,78, 325 (1997)). For the majority of the world population, drugtreatment for diabetes is not feasible and alternative treatments needto be evaluated.

Plants are important not only for the control of type 2 DM but also forits prevention, especially for people with elevated levels of bloodglucose and glucose intolerance who have a greater risk of developingdiabetes. Common spices such as cinnamon, cloves, and bay leaves displayinsulin potentiating activity in vitro (A. Khan et al., Biol. TraceElem. Res., 24, 183 (1990)). It was thought that these spices might alsohave high chromium (Cr) concentrations, because biologically activeforms of Cr potentiate insulin activity. However, there are nocorrelations between total Cr concentrations and insulin potentiatingactivity in these plant products (See, A. Khan et al., cited above).Only a small portion of the total Cr in biological systems is associatedwith insulin potentiating activity.

From an aqueous extract of commercial cinnamon, R. A. Anderson et al.,J. Agric. Food Chem., 52, 65 (2004) have identified polyphenolicpolymers that increase glucose metabolism roughly 20-fold in vitro inthe epididymal fat cell assay. These appear to be rather unique, becauseother cinnamon or similar compounds display little or no biologicalactivity. Additionally, approximately 50 plant extracts have also beeninvestigated in this assay, and none have shown activity equal to thatof cinnamon (C. L. Broadhurst et al., J. Agric. Food Chem., 48, 849(2000)).

Recently, R. A. Anderson et al., (cited above) extracted cinnamonsamples with acetic acid and ethanol and isolated fractions withinsulin-enhancing activity using HPLC. Spectral analysis indicated thepresence of, inter alia, doubly-linked aromatic polyphenols. Thestructures are shown below (Formula I).

The fractions containing these polyphenols, or A-type proanthocyanidins,were shown to have insulin-enhancing biological activity in an in vitroassay measuring the insulin-dependent effects on glucose metabolism.See, R. A. Anderson et al., J. Agric. Food Chem., 26, 1219 (1978). Thefractions also were active as antioxidants. N. W. Schoene et al., Nutr.Res., 20, 47 (2000). These same compounds have been shown to inhibitphosphotyrosine phosphatases in the insulin-receptor domain and toactivate insulin receptor kinase, and to function as a mimetic forinsulin in 3T3-L1 adipocytes. J. Imparl-Radosevich et al., Hormone Res.,50, 177 (1998); J. Am. Coll. Nutr., 20, 327 (2001). Water-solublepolymeric polyphenols from cinnamon have also been shown to inhibitproliferation and to alter cell cycle distribution patterns ofhematologic tumor cell lines. N. W. Schoene et al., Cancer Lett., 230,134 (2005).

However, compounds of Formula I are difficult to synthesize, as areintermediates useful in such syntheses. S. Morimoto et al., Chem. Pharm.Bull., 35, 4717 (1987) prepared proanthocyanins A-G (III) and A-7 (IV)in low yield by the oxidation of procyanidin B-5 (II) with hydrogenperoxide in the presence of sodium bicarbonate. See FIG. 1. A. Pomilo etal., Liebigs. Ann. Chem., 597 (1977) reacted flavylium perchloride (V)with (+) catechin in aqueous methanol to yield compound VII in 2-3%yield. (See FIG. 2). Therefore, there is a continuing need for methodsto prepare bioactive polyphenols, such as those derived from cinnamon.

SUMMARY OF THE INVENTION

The present invention provides a one-step synthesis of A-typeprocyanidins form benzopyrylium salts and phenols, such as flavins. Forexample, the present invention provides a method for the preparation ofa compound of Formula A:

wherein X, Y, X¹, Y¹, Z¹, X², Y², and Z² are individually H, OH, N(R)₂,(C₁-C₆)alkoxy, or (C₂-C₆)alkanoyloxy; G is H, OH, (C₁-C₆)alkoxy,(C₂-C₆)alkanoyloxy, N(R)₂ or NO₂; W is H, OH, (C₂-C₆)alkyl;(C₁-C₆)alkoxy, (C₁-C₆)hydroxyalkyl or (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl;Q is H or a single bond to C₈ of a compound of formula C wherein Q is H;each R is individually H, (C₁-C₄)alkyl, (C₂-C₆)alkanoyl or(C₆-C₁₄)arylC(O) wherein aryl, such as phenyl, can be substituted with1, 2 or 3 X; by reacting a compound of Formula B:

wherein An⁻ is a pharmaceutically acceptable anion, with a compound ofFormula (C):

in solution in an anhydrous (C₁-C₄)alkanol or mixture thereof, underambient conditions, e.g., at about 20°-50° C. for about 1-24 hours and;isolating the compound of Formula A.

The present invention also provides a method to prepare a compound ofFormula D:

wherein X, Y, Z, W, G and R are as defined above by reacting a compoundof Formula (B) with a compound of Formula (E):

wherein R¹ is OH or hydroxy(C₁-C₆)alkyl in solution in an anhydrous(C₁-C₄)alkanol or mixture thereof, under ambient conditions, e.g., atabout 20-50° C. for about 1-24 hours and; isolating the compound ofFormula D.

In both cases, the starting materials are dissolved at moderateconcentrations (0.02-0.2M) in an about 1:1 molar ratio, in methanol.Added water or aqueous buffer is not required. Yields are generally ≧70%after purification by simple chromatographic techniques, such as flashchromatography.

Novel compounds of Formula A or D are also within the scope of theinvention. The compounds are useful as intermediates to prepare complexproanthocyanidins, such as compounds shown in R. A. Anderson et al.(2004), cited above or 8, 9, 12, 13, 21, 20 and 14, as depicted in S.Morimoto et al., Chem. Pharm. Bull., 35, 4717 (1987). Certain of thesecompounds are useful as intermediates to make other compounds ofFormulas A or D, e.g., hydroxy groups can be converted into methoxygroups by reaction with CH₂N₂ or dimethyl sulfate, or esterified withalkanoyl or aroyl chlorides. Nitro groups can be reduced to amino groupsand acylated, alkylated or otherwise substituted.

The present methods are useful to make naturally-occurring polyphenolsand non-naturally occurring polyphenols and non-naturally occurringanalogs thereof that can have beneficial effects on glucose, insulin andblood lipids. Such compounds can be used to treat diabetes by enhancingthe effect of both in vivo and exogenously-administered insulin. Thus,compounds of Formula A and D can improve insulin receptor function byactivating insulin receptor kinase and inhibiting insulin receptorphosphatases, thus leading to increased insulin sensitivity, andimproved utilization of glucose by mammals, such as human diabetics inneed of such treatment. See, J. Impari-Radosevich et al., Hormone Res.,50, 177 (1998); K. J. Jarvill-Taylor et al., J. Am. Coll. Nutr., 20, 327(2001) and A. Khan et al., Diabetes Care, 26, 3215 (2003). Compounds ofFormula A and D can also alter proliferative signals that regulateprogression through the cell cycles of certain tumor cell lines, and maybe useful to treat cancer. See, N. W. Schoene et al., Cancer Lett., 230,134 (2000). Type A procyanidins have also been reported to exhibitantimicrobial, antiviral and antiprotozoal activity.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts a prior art synthetic route to proanthocyanins.

FIG. 2 depicts a prior art synthetic route to condense flavylium saltswith phenols.

FIG. 3 depicts the structures of some of the compounds prepared by thepresent method.

DETAILED DESCRIPTION OF THE INVENTION

Alkyl, alkoxy, hydroxyalkyl, alkanoyloxy, etc. denote both straight andbranched alkyl groups as well as cycloalkyl or (cycloalkyl)alkyl; butreference to an individual alkyl group such as Apropyl@ embraces onlythe straight chain group, a branched chain isomer such as Aisopropyl@being specifically referred to. Aryl denotes a phenyl substituent or anortho-fused bicyclic or tricyclic carbocyclic substituent having aboutnine to fourteen ring atoms in which at least one ring is aromatic.

It will be appreciated by those skilled in the art that compounds of theinvention having a chiral center may exist in and be isolated inoptically active and racemic forms. Some compounds may exhibitpolymorphism. It is to be understood that the present inventionencompasses any racemic, optically-active, polymorphic, orstereoisomeric form, or mixtures thereof, of a compound of theinvention, which possess the useful properties described herein, itbeing well known in the art how to prepare optically active forms (forexample, by resolution of the racemic form by recrystallizationtechniques, by synthesis from optically-active starting materials, bychiral synthesis, or by chromatographic separation using a chiralstationary phase) and how to determine anti-oxidant, anti-tumor orinsulin-potentiating activity using the standard tests referencedherein, or using other similar tests which are well known in the art.

Specific and preferred values listed below for radicals, substituents,and ranges, are for illustration only; they do not exclude other definedvalues or other values within defined ranges for the radicals andsubstituents.

Specifically, (C₁-C₆)alkyl can be methyl, ethyl, propyl, isopropyl,butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, hexyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, 2-cyclopropylethyl,2-cyclobutylethyl, or (C₁-C₆)alkoxy can be methoxy, ethoxy, propoxy,isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, orhexyloxy; acetyl, propanoyl or butanoyl; hydroxy(C₁-C₆)alkyl can bealkyl substituted with 1 or 2 OH groups, such as alkyl substituted with1 or 2 OH groups, such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxybutyl,4-hydroxybutyl, 3,4-dihydroxybutyl, 1-hydroxypentyl, 5-hydroxypentyl,1-hydroxyhexyl, or 6-hydroxyhexyl.

In compounds of Formulas A, B, C, D and E:

preferably, G is H, NO₂ or (C₁-C₄)alkoxy, e.g., methoxy;

preferably, X¹ is H, OH or (C₁-C₄)alkoxy, e.g., methoxy;

preferably, Y¹ is H, OH or (C₁-C₄)alkoxy, e.g., methoxy;

preferably, Z¹ is H, OH or (C₁-C₄)alkoxy, e.g., methoxy;

preferably, X and Y are H, OH, NH₂, or (C₁-C₄)alkoxy, e.g., methoxy;

preferably, X² and/or Y² are OH;

preferably, Z² is H or (C₁-C₄)alkoxy, e.g., methoxy;

preferably, W is H, OH, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, or(C₁-C₄)alkoxycarbonyl(C₁-C₂)alkyl;

preferably, N(R)₂ is NH₂;

preferably, each R is H or substituted phenylC(O), e.g.,3,4,5-trihydroxybenzoyl; and

preferably, R¹ is OH.

Specific embodiments include the preparation of compounds of Formulas Aor D wherein X¹ is H and Y¹ and Z¹ are OH or OCH₃; or wherein X¹, Y¹,and Z¹ are each OH or OCH₃; or wherein X¹ and Y¹ are H and Z¹ is OH.

Specific embodiments include the preparation of compounds of Formula Aor D, wherein X² and Y² are OH and Z² is H; or wherein each of X², Y²and Z² is OH.

Specific embodiments include the preparation of compounds of Formulas Aor D wherein W is H, OH or (C₁-C₄)alkyl, e.g., methyl or ethyl, or ismethoxycarbonylmethyl.

Specific embodiments include the preparation of compounds of Formulas Aor D wherein R is H.

Specific embodiments include the preparation of compounds of Formulas Aor D wherein G is H or NO₂.

Specific embodiments include the preparation of compounds of Formula Dwherein R¹ is OH and/or R is H.

In cases where compounds are sufficiently basic or acidic to form stablenontoxic acid or base salts, administration of the compounds as saltsmay be appropriate. Examples of pharmaceutically acceptable salts areorganic acid addition salts formed with acids which form a physiologicalacceptable anion, for example, tosylate, methanesulfonate, acetate,citrate, malonate, tartarate, succinate, benzoate, ascorbate,α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts mayalso be formed, including hydrochloride, sulfate, nitrate, bicarbonate,and carbonate salts.

Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound such as an amine with a suitable acid affording aphysiologically acceptable anion. Alkali metal (for example, sodium,potassium or lithium), alkaline earth metal (for example calcium ormagnesium) or zinc salts can also be made.

The compounds of Formula I can be formulated as pharmaceuticalcompositions and administered to a mammalian host, such as a humanpatient in a variety of forms adapted to the chosen route ofadministration, i.e., orally or parenterally, by intravenous,intramuscular, topical or subcutaneous routes, or by inhalation orinsufflation.

Thus, the present compounds may be systemically administered, e.g.,orally, in combination with a pharmaceutically acceptable vehicle suchas an inert diluent or an assimilable edible carrier. In view of thefact that useful compounds of Formulas A and D are either naturalproducts or analogs or prodrugs thereof, it is preferred to combine aneffective dose of one or more of said compounds with a foodstuff,intended for oral ingestion. Such foods can include those whichtypically contain sugar, such as cereals, “energy bars,” sports drinks,milk, flavored waters, shakes, breads, cookies, cakes, candy, and otherconfections.

They may also be enclosed in hard or soft shell gelatin capsules aspowders, pellets or suspensions or may be compressed into tablets. Fororal therapeutic administration, the active compound may be combinedwith one or more excipients and used in the form of ingestible tablets,buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers,and the like. Such compositions and preparations should contain at least0.1% of active compound. The percentage of the compositions andpreparations may, of course, be varied and may conveniently be betweenabout 2 to about 60% of the weight of a given unit dosage form. Theamount of active compound in such therapeutically useful compositions issuch that an effective dosage level will be obtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose, lactose or aspartame or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials may be present ascoatings or to otherwise modify the physical form of the solid unitdosage form. For instance, tablets, pills, or capsules may be coatedwith gelatin, wax, shellac or sugar and the like. A syrup or elixir maycontain the active compound, sucrose or fructose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. Of course, any material used in preparing anyunit dosage form should be pharmaceutically acceptable and substantiallynon-toxic in the amounts employed. In addition, the active compound maybe incorporated into sustained-release preparations and devices, such aspatches, infusion pumps or implantable depots.

The active compound may also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound or its salts can be prepared in water, optionally mixed with anontoxic surfactant. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, triacetin, and mixtures thereof and inoils. Under ordinary conditions of storage and use, these preparationscontain a preservative to prevent the growth of microorganisms.

Thus, for the treatment of diabetes, the present compounds can beprovided as kits, e.g., as premeasured vials or pre-loaded syringes incombination with separately packaged insulin-delivery devices, alongwith instructions for use of the kit to treat diabetes.

The pharmaceutical dosage forms suitable for injection, infusion orinhalation can include sterile aqueous solutions or dispersions. Sterilepowders can be prepared comprising the active ingredient which areadapted for the extemporaneous preparation of sterile injectable orinfusible solutions or dispersions, optionally encapsulated inliposomes. In all cases, the ultimate dosage form should be sterile,fluid and stable under the conditions of manufacture and storage. Theliquid carrier or vehicle can be a solvent or liquid dispersion mediumcomprising, for example, water, ethanol, a polyol (for example,glycerol, propylene glycol, liquid polyethylene glycols, and the like),vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.The proper fluidity can be maintained, for example, by the formation ofliposomes, by the maintenance of the required particle size in the caseof dispersions or by the use of surfactants. The prevention of theaction of microorganisms can be brought about by various antibacterialand antifungal agents, for example, parabens, chlorobutanol, phenol,sorbic acid, thimerosal, and the like. In many cases, it will bepreferable to include isotonic agents, for example, sugars, buffers orsodium chloride. Prolonged absorption of the injectable compositions canbe brought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate, cellulose ethers, andgelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfilter sterilization. In the case of sterile powders for the preparationof sterile injectable solutions, the preferred methods of preparationare vacuum drying and the freeze drying techniques, which yield a powderof the active ingredient plus any additional desired ingredient presentin the previously sterile-filtered solutions.

Useful dosages of the compounds of Formula I can be determined bycomparing their in vitro activity, and in vivo activity in animalmodels. Methods for the extrapolation of effective dosages in mice, andother animals, to humans are known to the art; for example, see U.S.Pat. No. 4,938,949.

The amount of the compound, or an active salt or derivative thereof,required for use in treatment will vary not only with the particularcompound or salt selected but also with the route of administration, thenature of the condition being treated and the age and condition of thepatient and will be ultimately at the discretion of the attendantphysician or clinician.

In general, however, a suitable dose will be in the range of from about0.5 to about 100 mg/kg, e.g., from about 10 to about 75 mg/kg of bodyweight per day, such as 3 to about 50 mg per kilogram body weight of therecipient per day, preferably in the range of 6 to 90 mg/kg/day, mostpreferably in the range of 15 to 60 mg/kg/day.

The compound is conveniently administered in unit dosage form; forexample, containing 5 mg to as much as 1-3 g, conveniently 10 to 1000mg, most conveniently, 50 to 500 mg of active ingredient per unit dosageform.

Ideally, the active ingredient should be administered to achieve peakplasma concentrations of the active compound of from about 0.5 to about75 μM, preferably, about 1 to 50 μM, most preferably, about 2 to about30 μM. This may be achieved, for example, by the intravenous injectionof a 0.05 to 5% solution of the active ingredient, optionally in saline.For example, as much as about 0.5-3 g of a compound of Formula I can bedissolved in about 125-500 ml of an intravenous solution comprising,e.g., 0.9% NaCl, and about 5-10% glucose. Such solutions can be infusedover an extended period of up to several hours, optionally inconjunction with other anti-viral agents, antibiotics, etc. The activeingredient can also be orally administered as a bolus containing about1-100 mg of the active ingredient. Desirable blood levels may bemaintained by continuous infusion to provide about 0.01-5.0 mg/kg/hr orby intermittent infusions containing about 0.4-15 mg/kg of the activeingredient(s).

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

The invention will be described further by reference to the followingdetailed Examples.

Example 1

Table 1 depicts the reaction of catechin hydrate (C-1) with variousflavylium salts (B-1) to yield compounds of Formula A-1.

TABLE 1

Yield Flavan G X¹ Y¹ Z¹ (%) A-1 (+)-catechin H H H H 82 A-1A(+)-catechin H H OH H 79 A-1B (+)-catechin H H OH OH 89 A-1C(+)-catechin H OH OH OH 80 A-1D (+)-catechin 6-NO₂ H OH H 83 A-1E(+)-catechin 6-NO₂ H OH OH 76 A-1F (+)-catechin 6-NO₂ OH OH OH 81 A-1G(+)-catechin 6-OH OH OH OH 47 A-1H (+)-catechin 8-OCH₃ H OH OH 70 A-1I(+)-catechin H H OCH₃ OCH₃ 83 A-1J (+)-catechin 7-OCH₃ OCH₃ OCH₃ OCH₃ 33A-1K (−)-epicatechin 6-NO₂ OH OH OH 81 A-1L (−)-Epigallocatechin 6-NO₂ HOH OH 86 A-1M gallate (−)-Epigallocatechin 6-NO₂ OH OH OH 71 A-1Ngallate

Example 2

Table 2 depicts the reaction of three 3-substituted flavins to yieldcompounds of Formula A-2.

TABLE 2

W¹ W² Yield (%) A-2 CH₃ CH₃ 75 A-2A C₂H₅ C₂H₅ 79 A-2B CH₂COOH CH₂COOCH₃83 A-2C

Example 3

Table 3 depicts the reaction of various flavylium perchloride salts withvarious phenols to yield compounds of Formula D-1. Generally, in allcases, the reactions proceeded to provide high (≧70%) yields of A-1, A-2or D-1 under ambient temperatures and pressures.

TABLE 3

R¹ G X¹ Y¹ Z¹ Yield (%) D-1 OH H H OH OH 76 D-1A OH 6-NO₂ H OH OH 80D-1B OH 6-NO₂ OH OH OH 82 D-1C H 6-NO₂ H OH OH 71 D-1D OH H OH OH OH 73D-1EA. General Procedure:

To a solution of catechin or other nucleophile in methanol (0.02-0.2 M)was added flavylium salt (1.0 to 1.2 equivalent) at room temperature.The mixture was stirred at room temperature to 50° C. for 1-24 hours(monitored by TLC and NMR). After the reaction finished, the mixture wasconcentrated and absorbed on a small amount of silica gel. The pureproduct was isolated by purification of the crude mixture using flashcolumn chromatography on silica gel with a mixture of hexane, ethylacetate and methanol as eluent.

B. A Typical Procedure for the Synthesis of Compound A-1A:

To a solution of (+)-catechin hydrate (C-1) (925 mg, 3.0 mmol) inmethanol (65 mL) was added 2-Phenylbenzopyrylium perchlorate salt (B-1;G, X¹, Y¹, Z¹═H) (920 mg, 3.0 mmol) at room temperature (25° C.). Thesolution was stirred at r.t. for 15 hours. The solution was concentratedand absorbed on a small amount of silica gel. The crude product waspurified on column chromatography on silica gel using hexane:ethylacetate:methanol (2:1:0-1:1.5:0.005) as eluent. 1.23 g compound A-1A wascollected in 82.2% yield. The product contains two stereoisomers in aratio of 60:40 indicated by NMR spectra.

C. Spectral Data:

Compound A-1A:

(2R,3S,8S,14S)-2-(3,4-dihydroxyphenyl)-8-phenyl-3,4-dihydro-2H,14H-8,14-methanochromeno[7,8-d][1,3]benzodioxocine-3,5-dioland(2R,3S,8R,14R)-2-(3,4-dihydroxyphenyl)-8-phenyl-3,4-dihydro-2H,14H-8,14-methanochromeno[7,8-d][1,3]benzodioxocine-3,5-diol

Yield=82%

Major isomer (60%)

¹H NMR (400 MHz, CD₃OD) δ 7.70-7.61 (m, 2H), 7.42-7.31 (m, 3H), 7.14(dd, J=7.6, 1.6 Hz, 1H), 7.10-6.98 (m, 2H), 6.93-6.72 (m, 4H), 6.09 (s,1H), 4.58 (d, J=8.0 Hz, 1H), 4.33 (t, J=3.0 Hz, 1H), 4.02 (m, 1H), 2.95(dd, J=16.4, 5.6 Hz, 1H), 2.51 (dd, J=16.4, 8.0 Hz, 1H), 2.22 (dd,J=13.2, 3.0 Hz, 1H), 2.18 (dd, J=13.2, 3.0 Hz, 1H).

Minor isomer (40%)

¹H NMR (400 MHz, CD₃OD) δ 7.70-7.61 (m, 2H), 7.42-7.31 (m, 3H), 7.26(dd, J=7.6, 1.6 Hz, 1H), 7.10-6.98 (m, 2H), 6.93-6.72 (m, 4H), 6.10 (s,1H), 4.71 (d, J=8.0 Hz, 1H), 4.27 (t, J=3.0 Hz, 1H), 3.96 (m, 1H), 2.87(dd, J=16.4, 5.6 Hz, 1H), 2.55 (dd, J=16.4, 8.0 Hz, 1H), 2.16 (dd,J=13.2, 3.0 Hz, 1H), 2.10 (dd, J=13.2, 3.0 Hz, 1H).

Major isomer (60%)

¹³C NMR (1100 MHz, CD₃OD) δ 155.74, 153.69, 152.71, 151.99, 146.39,146.33, 146.31, 143.34, 132.05, 129.59, 129.22, 129.13, 128.95, 128.58,128.33, 126.74, 122.04, 120.24, 116.76, 116.26, 115.52, 106.92, 102.83,99.92, 96.31, 82.97, 68.69, 34.53, 29.27, 28.00.

Minor isomer (40%)

¹³C NMR (1100 MHz, CD₃OD) δ 155.78, 153.64, 152.48, 152.03, 146.39,146.33, 146.31, 143.34, 132.21, 129.59, 129.22, 129.13, 128.95, 128.58,128.39, 126.74, 122.04, 120.36, 116.76, 116.04, 115.52, 106.75, 102.48,99.90, 96.22, 83.51, 68.76, 34.59, 28.63, 27.95.

HRMS (EI) m/z 496.1530 (M, 496.1522 calcd for C₃₀H₂₄O₇).

MS (EI) m/z 496 (11), 207 (100), 178 (39), 152 (58), 131 (70).

Compound A-1B:

(2R,3S,8S,14S)-2-(3,4-dihydroxyphenyl)-8-(4-hydroxyphenyl)-3,4-dihydro-2H,14H-8,14-methanochromeno[7,8-d][1,3]benzodioxocine-3,5-dioland(2R,3S,8R,14R)-2-(3,4-dihydroxyphenyl)-8-(4-hydroxyphenyl)-3,4-dihydro-2H,14H-8,14-methanochromeno[7,8-d][1,3]benzodioxocine-3,5-diol

Yield=79%

Major isomer (55%)

¹H NMR (400 MHz, CD₃OD) δ 7.54-7.48 (m, 2H), 7.12 (d, J=7.2 Hz, 1H),7.09-6.70 (m, 8H), 6.11 (s, 1H), 4.59 (d, J=8.4 Hz, 1H), 4.35 (t, J=3.0Hz, 1H), 3.98 (m, 1H), 3.01 (dd, J=16.4, 5.6 Hz, 1H), 2.52 (dd, J=16.4,8.4 Hz, 1H), 2.25 (dd, J=13.2, 3.0 Hz, 1H), 2.16 (dd, J=13.2, 3.0 Hz,1H).

Minor isomer (45%)

¹H NMR (400 MHz, CD₃OD) δ 7.54-7.48 (m, 2H), 7.27 (d, J=7.2 Hz, 1H),7.09-6.70 (m, 8H), 6.12 (s, 1H), 4.71 (d, J=8.4 Hz, 1H), 4.31 (t, J=3.0Hz, 1H), 4.04 (m, 1H), 2.92 (dd, J=16.4, 5.6 Hz, 1H), 2.57 (dd, J=16.4,8.4 Hz, 1H), 2.19 (dd, J=13.2, 3.0 Hz, 1H), 2.13 (dd, J=13.2, 3.0 Hz,1H).

Compound A-1C:

(2R,3S,8S,14S)-2-(3,4-dihydroxyphenyl)-8-(3,4-dihydroxyphenyl)-3,4-dihydro-2H,14H-8,14-methanochromeno[7,8-d][1,3]benzodioxocine-3,5-dioland(2R,3S,8R,14R)-2-(3,4-dihydroxyphenyl)-8-(3,4-dihydroxyphenyl)-3,4-dihydro-2H,14H-8,14-methanochromeno[7,8-d][1,3]benzodioxocine-3,5-diol

Yield=89%

Major isomer (60%)

¹H NMR (400 MHz, CD₃CN) δ 7.50-6.75 (m, 10H), 6.09 (s, 1H), 4.64 (d,J=8.0 Hz, 1H), 4.33 (br, 1H), 4.06-3.92 (m, 1H), 2.93-2.72 (m, 1H),2.57-2.42 (m, 1H), 2.32-2.08 (m, 2H).

Minor isomer (40%)

¹H NMR (400 MHz, CD₃CN) δ 7.50-6.75 (m, 10H), 6.10 (s, 1H), 4.73 (d,J=8.0 Hz, 1H), 4.25 (br, 1H), 4.06-3.92 (m, 1H), 2.93-2.72 (m, 1H),2.57-2.42 (m, 1H), 2.32-2.08 (m, 2H).

Compound A-1D:

5-[(2R,3S,8S,14S)-2-(3,4-dihydroxyphenyl)-3,5-dihydroxy-3,4-dihydro-2H,14H-8,14-methanochromeno[7,8-d][1,3]benzodioxocin-8-yl]benzene-1,2,3-trioland5-[(2R,3S,8R,14R)-2-(3,4-dihydroxyphenyl)-3,5-dihydroxy-3,4-dihydro-2H,14H-8,14-methanochromeno[7,8-d][1,3]benzodioxocin-8-yl]benzene-1,2,3-triol

Yield=80%

Major isomer (60%)

¹H NMR (400 MHz, CD₃OD) δ 7.12 (dd, J=7.6, 1.6 Hz, 1H), 7.09-6.70 (m,8H), 6.09 (s, 1H), 4.60 (d, J=8.0 Hz, 1H), 4.32 (t, J=2.8 Hz, 1H), 4.00(m, 1H), 2.95 (dd, J=16.4, 5.6 Hz, 1H), 2.53 (dd, J=16.4, 8.0 Hz, 1H),2.21 (dd, J=13.2, 2.8 Hz, 1H), 2.12 (dd, J=13.2, 2.8 Hz, 1H).

Minor isomer (40%)

¹H NMR (400 MHz, CD₃OD) δ 7.24 (dd, J=7.6, 1.2 Hz, 1H), 7.09-6.70 (m,8H), 6.09 (s, 1H), 4.74 (d, J=7.2 Hz, 1H), 4.25 (t, J=2.8 Hz, 1H), 4.04(m, 1H), 2.86 (dd, J=16.4, 5.2 Hz, 1H), 2.57 (dd, J=16.4, 8.0 Hz, 1H),2.15 (dd, J=13.2, 2.8 Hz, 1H), 2.08 (dd, J=13.2, 2.8 Hz, 1H).

Compound A-1E:

(2R,3S,8S,14S)-2-(3,4-dihydroxyphenyl)-8-(4-hydroxyphenyl)-12-nitro-3,4-dihydro-2H,14H-8,14-methanochromeno[7,8-d][1,3]benzodioxocine-3,5-dioland(2R,3S,8R,14R)-2-(3,4-dihydroxyphenyl)-8-(4-hydroxyphenyl)-12-nitro-3,4-dihydro-2H,14H-8,14-methanochromeno[7,8-d][1,3]benzodioxocine-3,5-diol

Yield=83%

Major isomer (60%)

¹H NMR (400 MHz, CD₃OD) δ 7.99 (d, J=2.8 Hz, 1H), 7.77 (dd, J=8.8, 2.8Hz, 1H), 7.52-7.40 (m, 2H), 7.08-6.78 (m, 6H), 6.07 (s, 1H), 4.59 (d,J=8.0 Hz, 1H), 4.34 (t, J=2.8 Hz, 1H), 4.11 (ddd, J=16.4, 8.0, 5.6 Hz,1H), 2.95 (dd, J=16.4, 5.6 Hz, 1H), 2.49 (dd, J=16.4, 8.4 Hz, 1H),2.26-2.01 (m, 2H).

Minor isomer (40%)

¹H NMR (400 MHz, CD₃OD) δ 8.14 (d, J=2.8 Hz, 1H), 7.84 (dd, J=8.8, 2.8Hz, 1H), 7.52-7.40 (m, 2H), 7.08-6.78 (m, 6H), 6.07 (s, 1H), 4.68 (d,J=8.0 Hz, 1H), 4.27 (t, J=2.8 Hz, 1H), 3.94 (ddd, J=16.4, 8.0, 5.6 Hz,1H), 2.88 (dd, J=16.4, 5.6 Hz, 1H), 2.54 (dd, J=16.4, 8.4 Hz, 1H),2.26-2.01 (m, 2H).

Major isomer (60%)

¹³C NMR (100 MHz, CD₃OD) δ 159.30, 158.88, 152.66, 151.51, 146.40,146.20, 142.41, 133.10, 131.50, 129.98, 127.07, 124.57, 124.36, 124.24,124.08, 121.07, 119.57, 117.34, 116.40, 115.90, 115.46, 105.56, 103.13,100.89, 96.34, 83.04, 68.06, 33.31, 29.09, 27.85.

Minor isomer (40%)

¹³C NMR (100 MHz, CD₃OD) δ 159.38, 158.88, 156.12, 152.50, 151.48,146.15, 145.85, 142.37, 133.06, 131.04, 129.84, 127.07, 124.57, 124.36,124.08, 121.07, 119.57, 117.42, 116.80, 116.26, 115.90, 105.38, 102.98,100.86, 96.36, 83.58, 68.79, 33.39, 28.79, 27.85.

Compound A-1F:

(2R,3S,8S,14S)-2,8-bis-(3,4-dihydroxyphenyl)-12-nitro-3,4-dihydro-2H,14H-8,14-methanochromeno[7,8-d][1,3]benzodioxocine-3,5-dioland(2R,3S,8R,14R)-2,8-bis-(3,4-dihydroxyphenyl)-12-nitro-3,4-dihydro-2H,14H-8,14-methanochromeno[7,8-d][1,3]benzodioxocine-3,5-diol

Yield=76%

Major isomer (60%)

¹H NMR (400 MHz, CD₃OD) δ 8.01 (br, 1H), 7.94 (dd, J=8.8, 2.0 Hz, 1H),7.18-6.78 (m, 7H), 6.09 (s, 1H), 4.61 (d, J=7.6 Hz, 1H), 4.37 (br, 1H),4.14 (m, 1H), 2.95 (dd, J=16.4, 5.2 Hz, 1H), 2.51 (dd, J=16.4, 8.4 Hz,1H), 2.32-2.06 (m, 2H).

Minor isomer (40%)

¹H NMR (400 MHz, CD₃OD) δ 8.16 (br, 1H), 7.91 (dd, J=8.8, 2.0 Hz, 1H),7.18-6.78 (m, 7H), 6.09 (s, 1H), 4.70 (d, J=7.6 Hz, 1H), 4.32 (br, 1H),3.95 (m, 1H), 2.89 (dd, J=16.4, 5.2 Hz, 1H), 2.55 (dd, J=16.4, 8.4 Hz,1H), 2.32-2.06 (m, 2H).

Major isomer (60%)

¹³C NMR (100 MHz, CD₃OD) δ 159.38, 156.16, 152.66, 151.54, 146.82,146.23, 145.89, 142.46, 133.76, 131.53, 130.07, 124.41, 124.29, 121.03,118.21, 117.34, 116.79, 116.24, 115.92, 115.39, 114.06, 105.57, 103.11,100.80, 96.30, 83.50, 68.09, 33.46, 29.05, 27.88.

Minor isomer (40%)

¹³C NMR (100 MHz, CD₃OD) δ 159.45, 156.16, 152.51, 151.54, 146.42,146.17, 145.89, 142.41, 133.76, 131.86, 129.93, 124.61, 124.12, 119.49,118.27, 117.41, 116.38, 116.24, 115.92, 115.39, 114.06, 105.40, 102.95,100.80, 96.30, 83.58, 68.78, 33.55, 28.73, 27.88.

Compound A-1G:

5-[(2R,3S,8S,14S)-2-(3,4-dihydroxyphenyl)-3,5-dihydroxy-12-nitro-3,4-dihydro-2H,14H-8,14-methanochromeno[7,8-d][1,3]benzodioxocin-8-yl]benzene-1,2,3-trioland5-[(2R,3S,8R,14R)-2-(3,4-dihydroxyphenyl)-3,5-dihydroxy-12-nitro-3,4-dihydro-2H,14H-8,14-methanochromeno[7,8-d][1,3]benzodioxocin-8-yl]benzene-1,2,3-triol

Yield=81%

Major isomer (60%)

¹H NMR (300 MHz, CD₃OD) δ 8.20 (d, J=2.7 Hz, 1H), 8.02 (dd, J=9.0, 2.7Hz, 1H), 7.13-6.70 (m, 6H), 6.10 (s, 1H), 4.65 (d, J=7.8 Hz, 1H), 4.47(t, J=2.4 Hz, 1H), 4.16 (m, 1H), 2.94 (dd, J=16.2, 5.6 Hz, 1H), 2.48(dd, J=16.2, 8.4 Hz, 1H), 2.43-2.23 (m, 2H).

Minor isomer (40%)

¹H NMR (300 MHz, CD₃OD) δ 8.08 (d, J=2.7 Hz, 1H), 8.05 (dd, J=9.0, 2.7Hz, 1H), 7.13-6.70 (m, 6H), 6.12 (s, 1H), 4.78 (d, J=7.8 Hz, 1H), 4.43(t, J=2.4 Hz, 1H), 3.96 (m, 1H), 2.85 (dd, J=16.2, 5.6 Hz, 1H), 2.54(dd, J=16.2, 8.4 Hz, 1H), 2.43-2.23 (m, 2H).

Compound A-1H:

(2R,3S,8S,14S)-2-(3,4-dihydroxyphenyl)-8-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H,14H-8,14-methanochromeno[7,8-d][1,3]benzodioxocine-3,5,12-trioland(2R,3S,8R,14R)-2-(3,4-dihydroxyphenyl)-8-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H,14H-8,14-methanochromeno[7,8-d][1,3]benzodioxocine-3,5,12-triol

Yield=47%

Major isomer (60%)

¹H NMR (300 MHz, CD₃COCD₃) δ 8.40-6.51 (m, 8H), 6.10 (s, 1H), 4.69 (d,J=7.8 Hz, 1H), 4.27 (t, J=2.8 Hz, 1H), 4.04-3.84 (m, 1H), 3.02-2.86 (m,1H), 2.63-2.47 (m, 1H), 2.26-2.10 (m, 2H).

Minor isomer (40%)

¹H NMR (300 MHz, CD₃COCD₃) δ 8.40-6.51 (m, 8H), 6.12 (s, 1H), 4.67 (d,J=7.8 Hz, 1H), 4.18 (t, J=2.8 Hz, 1H), 4.04-3.84 (m, 1H), 3.02-2.86 (m,1H), 2.63-2.47 (m, 1H), 2.26-2.10 (m, 2H).

Compound A-1I:

(2R,3S,8S,14R)-2,8-bis(3,4-dihydroxyphenyl)-10-methoxy-3,4-dihydro-2H,14H-8,14-methanochromeno[7,8-d][1,3]benzodioxocine-3,5-dioland(2R,3S,8R,14S)-2,8-bis(3,4-dihydroxyphenyl)-10-methoxy-3,4-dihydro-2H,14H-8,14-methanochromeno[7,8-d][1,3]benzodioxocine-3,5-diol

Yield=70%

Major isomer (65%)

¹H NMR (300 MHz, CD₃COCD₃) δ 7.30-6.65 (m, 9H), 6.13 (s, 1H), 4.60 (d,J=7.8 Hz, 1H), 4.35 (t, J=3.0 Hz, 1H), 4.20-3.94 (m, 1H), 3.75 (s, 3H),3.02 (dd, J=16.5, 5.6 Hz, 1H), 2.55 (dd, J=16.5, 8.7 Hz, 1H), 2.30 (dd,J=13.2, 3.0 Hz, 1H), 2.18 (dd, J=13.2, 3.0 Hz, 1H).

Minor isomer (35%)

¹H NMR (300 MHz, CD₃COCD₃) δ 7.30-6.65 (m, 9H), 6.14 (s, 1H), 4.73 (d,J=8.1 Hz, 1H), 4.28 (t, J=3.0 Hz, 1H), 4.20-3.94 (m, 1H), 3.77 (s, 3H),2.95 (dd, J=16.5, 5.6 Hz, 1H), 2.59 (dd, J=16.5, 8.7 Hz, 1H), 2.25 (dd,J=13.2, 3.0 Hz, 1H), 2.15 (dd, J=13.2, 3.0 Hz, 1H).

Compound A-1J:

(2R,3S,8R,14R)-2-(3,4-dihydroxyphenyl)-8-(3,4-dimethoxyphenyl)-3,4-dihydro-2H,14H-8,14-methanochromeno[7,8-d][1,3]benzodioxocine-3,5-dioland(2R,3S,8S,14S)-2-(3,4-dihydroxyphenyl)-8-(3,4-dimethoxyphenyl)-3,4-dihydro-2H,14H-8,14-methanochromeno[7,8-d][1,3]benzodioxocine-3,5-diol

Yield=83%

Major isomer (55%)

¹H NMR (400 MHz, CD₃COCD₃) δ 7.38-6.74 (m, 10H), 6.16 (s, 1H), 4.62 (d,J=8.0 Hz, 1H), 4.38 (t, J=3.0 Hz, 1H), 4.13 (m, 1H), 3.85 (m, 3H), 3.83(m, 3H), 3.03 (dd, J=16.4, 5.6 Hz, 1H), 2.57 (dd, J=16.4, 8.0 Hz, 1H),2.34 (dd, J=13.6, 3.0 Hz, 1H), 2.25 (dd, J=13.6, 3.0 Hz, 1H).

Minor isomer (45%)

¹H NMR (400 MHz, CD₃COCD₃) δ 7.38-6.74 (m, 10H), 6.18 (s, 1H), 4.73 (d,J=8.0 Hz, 1H), 4.30 (t, J=3.0 Hz, 1H), 4.01 (m, 1H), 3.84 (m, 3H), 3.83(m, 3H), 2.97 (dd, J=16.4, 5.2 Hz, 1H), 2.61 (dd, J=16.4, 8.0 Hz, 1H),2.28 (dd, J=13.6, 3.0 Hz, 1H), 2.22 (dd, J=13.6, 3.0 Hz, 1H).

Major isomer (55%)

¹³C NMR (100 MHz, CD₃COCD₃) δ 156.20, 154.25, 153.39, 152.68, 150.91,146.75, 146.64, 146.48, 133.09, 132.82, 129.18, 128.99, 122.56, 121.17,119.97, 116.88, 116.32, 116.13, 113.07, 107.63, 103.59, 100.36, 97.13,83.72, 69.29, 57.17, 57.10, 34.90, 29.95, 28.51.

Minor isomer (45%)

¹³C NMR (100 MHz, CD₃COCD₃) δ 156.17, 154.31, 153.22, 152.70, 151.46,146.78, 146.70, 140.54, 133.01, 129.71, 129.54, 129.03, 121.29, 117.55,116.72, 116.67, 116.41, 111.79, 107.46, 103.35, 100.34, 97.13, 96.40,84.38, 69.11, 57.17, 57.10, 34.98, 29.66, 28.51.

Compound A-1K:

(2R,3S,8R,14R)-2-(3,4-dihydroxyphenyl)-11-methoxy-8-(3,4,5-trimethoxyphenyl)-3,4-dihydro-2H,14H-8,14-methanochromeno[7,8-d][1,3]benzodioxocine-3,5-dioland(2R,3S,8S,14S)-2-(3,4-dihydroxyphenyl)-11-methoxy-8-(3,4,5-trimethoxyphenyl)-3,4-dihydro-2H,14H-8,14-methanochromeno[7,8-d][1,3]benzodioxocine-3,5-diol

Yield=33%

Major isomer (60%)

¹H NMR (400 MHz, CD₃COCD₃) δ 7.20-6.73 (m, 8H), 6.14 (s, 1H), 4.61 (d,J=8.0 Hz, 1H), 4.34 (t, J=3.2 Hz, 1H), 3.97 (m, 1H), 3.88 (m, 6H), 3.76(m, 3H), 3.71 (m, 3H), 2.91 (dd, J=16.4, 5.6 Hz, 1H), 2.53 (dd, J=16.4,8.4 Hz, 1H), 2.34 (dd, J=13.6, 3.2 Hz, 1H), 2.25 (dd, J=13.6, 3.2 Hz,1H).

Minor isomer (40%)

¹H NMR (400 MHz, CD₃COCD₃) δ 7.20-6.73 (m, 8H), 6.15 (s, 1H), 4.70 (d,J=8.0 Hz, 1H), 4.24 (t, J=3.2 Hz, 1H), 4.09 (m, 1H), 3.87 (m, 6H), 3.76(m, 3H), 3.74 (m, 3H), 3.01 (dd, J=16.4, 5.6 Hz, 1H), 2.57 (dd, J=16.4,8.4 Hz, 1H), 2.29 (dd, J=13.6, 3.2 Hz, 1H), 2.23 (dd, J=13.6, 3.2 Hz,1H).

Compound A-1L:

5-[(2R,3R,8S,14S)-2-(3,4-dihydroxyphenyl)-3,5-dihydroxy-12-nitro-3,4-dihydro-2H,14H-8,14-methanochromeno[7,8-d][1,3]benzodioxocin-8-yl]benzene-1,2,3-trioland5-[(2R,3R,8R,14R)-2-(3,4-dihydroxyphenyl)-3,5-dihydroxy-12-nitro-3,4-dihydro-2H,14H-8,14-methanochromeno[7,8-d][1,3]benzodioxocin-8-yl]benzene-1,2,3-triol

Yield=81%

Major isomer (60%)

¹H NMR (300 MHz, CD₃OD) δ 8.26 (d, J=2.7 Hz, 1H), 8.03-6.94 (m, 7H),6.55 (s, 1H), 4.70-4.48 (m, 2H), 4.08 (m, 1H), 2.94 (dd, J=16.2, 5.6 Hz,1H), 2.53 (dd, J=16.2, 9.6 Hz, 1H), 2.38-2.19 (m, 2H).

Minor isomer (40%)

¹H NMR (300 MHz, CD₃OD) δ 8.05 (d, J=2.7 Hz, 1H), 8.03-6.94 (m, 7H),6.56 (s, 1H), 4.70-4.48 (m, 2H), 3.88 (m, 1H), 2.99 (dd, J=16.2, 5.6 Hz,1H), 2.60 (dd, J=16.2, 9.6 Hz, 1H), 2.38-2.19 (m, 2H).

Compound A-1M:

(2R,3R,8S,14S)-2,8-bis-(3,4-dihydroxyphenyl)-5-hydroxy-12-nitro-3,4-dihydro-2H,14H-8,14-methanochromeno[7,8-d][1,3]benzodioxocin-3-yl3,4,5-trihydroxybenzoate and(2R,3R,8R,14R)-2,8-bis-(3,4-dihydroxyphenyl)-5-hydroxy-12-nitro-3,4-dihydro-2H,14H-8,14-methanochromeno[7,8-d][1,3]benzodioxocin-3-yl3,4,5-trihydroxybenzoate

Yield=86%

Major isomer (70%)

¹H NMR (400 MHz, CD₃COCD₃) δ 8.18 (d, J=2.8 Hz, 1H), 8.02 (dd, J=9.2,2.8 Hz, 1H), 7.27-6.70 (m, 8H), 6.18 (s, 1H), 5.59 (m, 1H), 5.20 (s,1H), 4.75 (t, J=3.0 Hz, 1H), 3.11 (dd, J=17.2, 4.4 Hz, 1H), 3.01 (dd,J=17.2, 2.4 Hz, 1H), 2.54 (dd, J=13.6, 3.2 Hz, 1H), 2.45 (dd, J=13.6,3.0 Hz, 1H).

Minor isomer (30%)

¹H NMR (400 MHz, CD₃COCD₃) δ 8.54 (d, J=2.8 Hz, 1H), 8.09 (dd, J=9.2,2.8 Hz, 1H), 7.27-6.70 (m, 8H), 6.21 (s, 1H), 5.59 (m, 1H), 5.27 (s,1H), 4.65 (t, J=3.0 Hz, 1H), 3.20-2.80 (m, 2H), 2.44 (m, 2H).

Compound A-1N:

(2R,3R,8S,14S)-2-(3,4-dihydroxyphenyl)-5-hydroxy-12-nitro-8-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H,14H-8,14-methanochromeno[7,8-d][1,3]benzodioxocin-3-yl3,4,5-trihydroxybenzoate and(2R,3R,8R,14R)-2-(3,4-dihydroxyphenyl)-5-hydroxy-12-nitro-8-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H,14H-8,14-methanochromeno[7,8-d][1,3]benzodioxocin-3-yl3,4,5-trihydroxybenzoate

Yield=71%

Major isomer (60%)

¹H NMR (400 MHz, CD₃OD) δ 8.42 (d, J=2.8 Hz, 1H), 8.07 (dd, J=8.8, 2.8Hz, 1H), 7.12-6.48 (m, 7H), 6.12 (s, 1H), 5.53 (m, 1H), 5.18 (s, 1H),4.57 (t, J=3.0 Hz, 1H), 3.16-2.71 (m, 2H), 2.49-2.26 (m, 2H).

Minor isomer (40%)

¹H NMR (400 MHz, CD₃OD) δ 8.17 (d, J=2.8 Hz, 1H), 8.00 (dd, J=8.8, 2.8Hz, 1H), 7.12-6.48 (m, 7H), 6.11 (s, 1H), 5.57 (m, 1H), 5.10 (s, 1H),4.67 (t, J=3.0 Hz, 1H), 3.16-2.71 (m, 2H), 2.49-2.26 (m, 2H).

Compound A-2A:

(2R,3S,8S,14S,15S)-2,8-bis-(3,4-dihydroxyphenyl)-15-methyl-12-nitro-3,4-dihydro-2H,14H-8,14-methanochromeno[7,8-d][1,3]benzodioxocine-3,5-dioland(2R,3S,8R,14R,15R)-2,8-bis-(3,4-dihydroxyphenyl)-15-methyl-12-nitro-3,4-dihydro-2H,14H-8,14-methanochromeno[7,8-d][1,3]benzodioxocine-3,5-diol

Yield=75%

Major isomer (55%)

¹H NMR (400 MHz, CD₃OD) δ 8.00 (d, J=2.8 Hz, 1H), 7.97 (dd, J=8.8, 2.8Hz, 1H), 7.06-6.79 (m, 7H), 6.14 (s, 1H), 4.62 (d, J=8.0 Hz, 1H), 4.15(m, 1H), 4.14 (m, 1H), 2.97 (dd, J=16.4, 5.6 Hz, 1H), 2.53 (dd, J=16.4,8.4 Hz, 1H), 2.35 (dd, J=7.2, 2.4 Hz, 1H), 0.78 (d, J=6.8 Hz, 3H).

Minor isomer (45%)

¹H NMR (400 MHz, CD₃OD) δ 8.15 (d, J=2.8 Hz, 1H), 7.90 (dd, J=8.8, 2.8Hz, 1H), 7.06-6.79 (m, 7H), 6.15 (s, 1H), 4.70 (d, J=8.0 Hz, 1H), 4.13(m, 1H), 3.95 (ddd, J=13.6, 8.0, 5.6 Hz, 1H), 2.90 (dd, J=16.4, 5.6 Hz,1H), 2.56 (dd, J=16.4, 8.4 Hz, 1H), 2.32 (dd, J=7.2, 2.4 Hz, 1H), 0.74(d, J=6.8 Hz, 3H).

Compound A-2B:

(2R,3S,8S,14S,15S)-2,8-bis-(3,4-dihydroxyphenyl)-15-ethyl-12-nitro-3,4-dihydro-2H,14H-8,14-methanochromeno[7,8-d][1,3]benzodioxocine-3,5-dioland(2R,3S,8R,14R,15R)-2,8-bis-(3,4-dihydroxyphenyl)-15-ethyl-12-nitro-3,4-dihydro-2H,14H-8,14-methanochromeno[7,8-d][1,3]benzodioxocine-3,5-diol

Yield=79%

Major isomer (55%)

¹H NMR (400 MHz, CD₃OD) δ 8.20 (d, J=2.8 Hz, 1H), 7.90 (dd, J=8.8, 2.8Hz, 1H), 7.11-6.80 (m, 7H), 6.16 (s, 1H), 4.72 (d, J=8.0 Hz, 1H), 4.34(d, J=2.0 Hz, 1H), 3.98 (ddd, J=13.6, 8.0, 5.6 Hz, 1H), 2.92 (dd,J=16.4, 5.6 Hz, 1H), 2.58 (dd, J=16.4, 8.4 Hz, 1H), 2.11 (m, 1H), 1.04(m, 2H), 0.70 (t, J=7.0 Hz, 3H).

Minor isomer (45%)

¹H NMR (400 MHz, CD₃OD) δ 8.04 (d, J=2.8 Hz, 1H), 7.86 (dd, J=8.8, 2.8Hz, 1H), 7.11-6.80 (m, 7H), 6.15 (s, 1H), 4.68 (d, J=8.0 Hz, 1H), 4.39(d, J=2.4 Hz, 1H), 4.14 (ddd, J=13.6, 8.0, 5.6 Hz, 1H), 2.96 (dd,J=16.4, 5.6 Hz, 1H), 2.54 (dd, J=16.4, 8.4 Hz, 1H), 2.11 (m, 1H), 1.13(m, 2H), 0.77 (t, J=7.0 Hz, 3H).

Compound A-2C:

Methyl[(2R,3S,8S,14S,15S)-2,8-bis-(3,4-dihydroxyphenyl)-12-nitro-3,4-dihydro-2H,14H-8,14-methanochromeno[7,8-d][1,3]benzodioxocine-15-yl]acetateand Methyl[(2R,3S,8R,14R,15R)-2,8-bis-(3,4-dihydroxyphenyl)-12-nitro-3,4-dihydro-2H,14H-8,14-methanochromeno[7,8-d][1,3]benzodioxocine-15-yl]acetate

Yield=83%

Major isomer (70%)

¹H NMR (400 MHz, CD₃OD) δ 8.07 (d, J=2.8 Hz, 1H), 7.95 (dd, J=8.8, 2.8Hz, 1H), 7.10-6.70 (m, 7H), 6.17 (s, 1H), 4.71 (d, J=7.2 Hz, 1H), 4.36(d, J=2.0 Hz, 1H), 4.15 (ddd, J=13.2, 7.2, 5.6 Hz, 1H), 3.51 (s, 3H),2.86 (m, 1H), 2.79 (m, 1H), 2.53 (dd, J=16.4, 8.0 Hz, 1H), 2.19 (m, 1H).

Minor isomer (30%)

¹H NMR (400 MHz, CD₃OD) δ 8.18 (d, J=2.8 Hz, 1H), 7.99 (dd, J=8.8, 2.8Hz, 1H), 7.10-6.70 (m, 7H), 6.19 (s, 1H), 4.74 (d, J=7.2 Hz, 1H), 4.32(d, J=2.4 Hz, 1H), 3.98 (m, 1H), 3.45 (s, 3H), 2.89 (m, 1H), 2.79 (m,1H), 2.57 (dd, J=16.4, 8.0 Hz, 1H), 2.19 (m, 1H).

Compound D-1A:

(±)-6-(3,4-dihydroxyphenyl)-12H-6,12-methanodibenzo[d,g][1,3]dioxocine-1,3-diol

Yield=76%

¹H NMR (400 MHz, CD₃COCD₃) δ 7.42 (dd, J=7.2, 1.2 Hz, 1H), 7.31 (m, 2H),7.10 (ddd, J=10, 8.4, 2.0 Hz, 1H), 7.01 (d, 8.4 Hz, 1H), 6.92 (d, J=8.4Hz, 1H), 6.87 (ddd, J=8.4, 7.2, 0.8 Hz, 1H), 6.05 (d, J=2.4 Hz, 1H),6.02 (d, J=2.4 Hz, 1H), 4.42 (t, J=2.8 Hz, 1H), 2.31 (t, J=2.8 Hz, 2H).

Compound D-1B:

(±)-6-(3,4-dihydroxyphenyl)-10-nitro-12H-6,12-methanodibenzo[d,g][1,3]dioxocine-1,3-diol

Yield=80%

¹H NMR (400 MHz, CD₃COCD₃) δ 8.30 (d, J=2.8 Hz, 1H), 8.02 (dd, J=8.8,2.8 Hz, 1H), 7.25 (d, J=2.8 Hz, 1H), 7.10 (m, 2H), 6.92 (d, J=8.8 Hz,1H), 6.10 (d, J=2.8 Hz, 1H), 6.05 (d, J=2.8 Hz, 1H), 4.53 (t, J=2.8 Hz,1H), 2.39 (t, J=2.8 Hz, 2H).

¹³C NMR (100 MHz, CD₃COCD₃) δ 159.94, 159.23, 156.55, 154.62, 147.36,146.44, 143.06, 134.47, 130.75, 125.12, 124.91, 119.13, 118.35, 116.66,114.88, 106.28, 101.39, 96.84, 96.29, 34.15, 28.44.

Compound D-1C:

(±)-5-(1,3-dihydroxy-10-nitro-12H-6,12-methanodibenzo[d,g][1,3]dioxocin-6-yl)benzene-1,2,3-triol

Yield=82%

¹H NMR (400 MHz, CD₃COCD₃) δ 8.30 (d, J=2.8 Hz, 1H), 8.02 (dd, J=8.8,2.8 Hz, 1H), 7.10 (d, J=8.8 Hz, 1H), 6.79 (s, 2H), 6.08 (d, J=2.0 Hz,1H), 6.04 (d, J=2.0 Hz, 1H), 4.54 (t, J=2.8 Hz, 1H), 2.37 (t, J=2.8 Hz,2H).

Compound D-1D:

(±)-5-(1-hydroxy-10-nitro-12H-6,12-methanodibenzo[d,g][1,3]dioxocin-6-yl)benzene-1,2,3-triol

Yield=71%

¹H NMR (400 MHz, CD₃COCD₃) δ 8.33 (d, J=2.8 Hz, 1H), 8.05 (dd, J=9.2,2.8 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 7.12 (d, J=9.2 Hz, 1H), 6.80 (s,2H), 6.47 (ddd, J=7.2, 4.4, 2.4 Hz, 2H), 4.38 (t, J=2.8 Hz, 1H), 2.44(dd, J=2.8, 1.8 Hz, 2H).

Compound D-1E:

(±)-5-(1,3-dihydroxy-12H-6,12-methanodibenzo[d,g][1,3]dioxocin-6-yl)benzene-1,2,3-triol

Yield=73%

¹H NMR (300 MHz, CD₃OD) δ 7.36 (dd, J=7.5, 1.5 Hz, 1H), 7.06 (ddd,J=8.7, 6.9, 1.5 Hz, 1H), 6.85 (m, 2H), 6.74 (s, 2H), 5.83 (s, 2H), 4.33(t, J=2.8 Hz, 1H), 2.17 (t, J=2.8 Hz, 2H).

The invention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

All patents, patent applications, and literature cited in thespecification are hereby incorporated by reference in their entirety. Inthe case of any inconsistencies, the present disclosure, including anydefinitions therein will prevail.

What is claimed is:
 1. A compound of Formula A:

wherein X, Y, X¹, Y¹, Z¹ and X², Y², and Z² are each individually H, OH,N(R)₂, (C₁-C₆)alkoxy, or (C₂-C₆)alkanoyloxy; G is OH, (C₁-C₆)alkoxy,(C₂-C₆)alkanoyloxy, N(R)₂, or NO₂; W is H, OH, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₁-C₆)hydroxyalkyl or(C₁-C₆)alkoxylcarbonyl(C₁-C₆)alkyl; Q is H or a single bond to C₈ offormula (C):

and each R is individually H, (C₁-C₄)alkyl, (C₂-C₆)alkanoyl, or(C₆-C₁₄)arylC(O), wherein aryl is optionally substituted with 1, 2, or 3X.
 2. The compound of claim 1 wherein G is H, NO₂, or (C₁-C₄)alkoxy. 3.The compound of claim 1 wherein X and Y are H, OH, or (C₁-C₄)alkoxy. 4.The compound of claim 1 wherein X¹, Y¹, and Z¹ are H, OH, or(C₁-C₄)alkoxy.
 5. The compound of claim 1 wherein X¹ is H, and Y¹ and Z²are OH or OCH₃.
 6. The compound of claim 1 wherein each of X², Y², andZ² is OH.
 7. The compound of claim 1 wherein W is H, OH, (C₁-C₄)alkyl,(C₁-C₄)alkoxy, or (C₁-C₄)alkoxycarbonyl(C₁-C₂)alkyl.
 8. The compound ofclaim 1 wherein Q is H.
 9. The compound of claim 1 wherein each R isindividually H or substituted phenylC(O).